Electroactive bioadhesive compositions

ABSTRACT

The present invention relates to electrochemically initiated bioadhesive compositions comprising biocompatible polymers containing derivatives of diazonium, arylsulfonium, or diaryliodonium in general, and to their use in tissue fixation, in particular.

FIELD OF THE INVENTION

The present invention relates to electrochemically initiated bioadhesivecompositions comprising biocompatible polymers containing derivatives ofdiazonium, arylsulfonium, or diaryliodonium in general, and to their usein tissue fixation, in particular.

BACKGROUND OF THE INVENTION

Current methods of tissue fixation leave much to be desired; essentiallyrelying on technologies developed from the clothing and carpentryindustries. Screws, pins, wires, sutures, and buttress plates, areexamples of bone and soft tissue fixation implants. These devices havemany disadvantages, including the need for subsequent operations forremoval and interference with mobility and growth impediments in youths.They also have high rates of complications, such as infection and tissueinflammation.

With the market value of tissue fixation devices estimated atapproximately four billion dollars, many attempts have been made toimprove upon these implants. Resorbable implants have made inroads inaddressing some of the issues above, however they still have problemswith the destructive nature of the mechanical fixation. For example, thetrauma induced by resorbable suturing on intestinal tissue upregulatesenzymes that breakdown collagen (the structural component) for up to 4days post-procedure—weakening the intestine tissue and raising theprobabilities of tears and intestinal leakages—but it's still thestandard operating procedure for intestinal anastomoses. Intestinalanastomoses are typically performed for treatment of colorectal cancer.

‘Gluing’ soft-tissues and biomaterials together is far more convenientthan sutures and conventional tissue fixation, but development of asuitable bioadhesive has yet to be fully realized. Bioadhesive ‘glues’are a significant engineering hurdle in numerous fields including woundclosures, implantable electronics, meshes for abdominal surgeries, andtissue engineering transplants. Medical grade cyanoacrylates, forexample Dermabond® and Super Glue®, and fibrin tissue adhesives, forexample Tisseal® and Evicel®, are currently the only commerciallyavailable and FDA approved bioadhesives that have addressed soft tissuefixation. Unfortunately, they trade adhesive strength forbiocompatibility or vice versa. Cyanoacrylates typically have strongtissue adhesion, but are relatively inflexible. Their brittleness,combined with local tissue toxicity and incapability of local drugdelivery limits them to skin and other topical adhesions. Fibrin-basedtissue adhesives have many shortcomings as well. Their bioadhesion is‘hydrogel’ weak, has potential neurotoxicity complications and seriousreligious concerns due to the predominantly human (or bovine) fibrinogenand thrombin sources. Due to their weak mechanical properties, fibrintissues adhesives are best suited for control of bleeding.

WO 2010/100410 and WO 2010/100413 disclose functionalized diazoderivatives, including diazopyruvate, and their use for producing achemically-bound three-dimensional network on or within a substrate.

WO 2009/097152 relates to calcium-reactive amines and acrylic ormethacrylic ester monomers adhesives, and use thereof for adheringdental and medical biomaterials to hard tissues via a molecular bridgeformed from to hard tissues such as enamel, dentin, and bone.

JP 2007254307A describes a dental adhesive that comprises of apolymerizable monomer including an acidic group-containing polymerizablemonomer, water and a polymerization initiator comprising a photo acidgenerator, an oxidation type photoradical generator. The photo acidgenerator is preferably a diaryl iodonium salt-based compound, but theactivation of the adhesive is by photo-activation.

WO 2008/023170 describes a group of diazo compounds used as aryl carbeneprecursors for use in the process of producing a substrate having anadhesive surface, which allows the substrate to adhere to othermaterials to be tailored.

WO 2008/121033 provides an adhesive for facilitating the adhesionbetween an electroactive polymer and a substrate, wherein the adhesiveconsists of a platinum or an alloy comprising platinum.

EP 0330344 relates to use of crosslinked collagen as a bioadhesive forsutureless closures of the skin and eye or as a superhydrated materialfor contact lenses, moist bandage contact lens, lens or corneal implantmaterial, or as a drug delivery agent. According to EP 0330344,collagen, which is an example of amino-acid containing polymers, iscrosslinked into a highly molecularly crosslinked product uponphotoactivation with photoactive crosslinking reagents, such as diazo orazide derivatives.

Failure of soft tissue bioadhesives to address local tissue fixation andbiocompatibility has prompted urgent need for a new bioadhesive thatallows biomaterials to be adhered onto soft tissues while maintaining ahigh level of biocompatibility and adhesive strength.

SUMMARY OF THE INVENTION

Various embodiments of the invention provide electrochemically activatedor electroactive bioadhesive compositions containing diazonium,arylsulfonium, or diaryliodonium and the respective derivatives, andtheir use in tissue fixation.

In one embodiment, an electroactive polymer comprises a biocompatiblepolymer comprising a single strand of repeating-units and up to 5,000electroactive groups covalently attached to said strand, wherein saidelectroactive polymer has a molecular weight of up to 3 million Daltons,and wherein said electroactive groups are derivatives of diazoniumsalts, derivatives of arylsulfonium salts, derivatives of diaryliodoniumsalts, or combination thereof.

In particular embodiments, said biocompatible polymer can be anybioresorbable polymer that has been FDA-approved as a medical deviceselected from the group consisting of polyethylene glycol (PEG), PEGfatty acid esters, poly-L-lactic acid (PLLA), poly(lactide-co-glycolide)(PLGA), poly caprolactone (PCL), polyvinyl pyrrolidone (PVP), polyvinylalcohol (PVA), collagen, chitosan, hydroxy propyl cellulose, polyamides,polyglycerol esters of fatty acids, polysaccharides, polyesters, andcombinations thereof. The polysaccharide is selected from the groupconsisting of dextran, chitosan, heparin, hyaluronic acid, alginates,starch, glycogen, amylose, amylopectin, cellulose, xylan, and numerousother natural and synthetic polysaccharides.

In a further embodiment, the electroactive diazonium derivative is acompound of the following formula:

wherein

X is an inorganic or organic anion selected from the group consisting ofanion of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻, PF₆, HgBr₂,HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate;

R is a bond or 5-7 membered saturated cyclic or heterocyclic, aromaticor heteroaromatic ring unsubstituted or mono-, di- or tri-substitutedwith:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

Y is a bond or saturated and unsaturated C₁-C₅₀₀ straight-chain orbranched alkyl, alkenyl or alkynyl group, wherein said chain mayoptionally incorporate at least one hetero atom, and may also compriseat least one substituent; and

Z is any suitable functional group selected from the group consisting ofhalogen, amino, cyano, hydroxy, aldehyde, alkoxycarbonyl, N-amide,N-hydroxysuccinimide ester, maleimide, and thiol.

In specific embodiments, the electroactive diazonium derivative can beselected from the list of:

-   4-(dimethylamino)-benzene-diazonium salt;-   2-chloro-benzene-diazonium salt;-   1-naphthalene-diazonium salt;-   4-anilino-benzene-diazonium salt;-   3,5-dichloro-benzene-diazonium salt;-   1-pyrene-diazonium salt;-   4-Methoxy-benzene-diazonium salt;-   4-bromo-benzene-diazonium salt;-   4-formyl-benzene-diazonium salt;-   4-Nitro-benzene-diazonium salt;-   Fast Red TR salt;-   Variamine blue B salt;-   4-[ethyl(2-hydroxyethyl)amino]-benzene-diazonium salt;-   4-(diethylamino)-2-methyl-benzene-diazonium salt;-   4-(ethylamino)-3-methyl-benzene-diazonium salt;-   5-chloro-2-methoxy-benzene-diazonium salt;-   3-methyl-4-nitro-benzene-diazonium salt;-   bis[4-(diethylamino)-2-methyl-benzene-diazonium] salt;-   2,4-dichloro-benzene-diazonium salt;-   2-methoxy-4-nitro-benzene-diazonium salt;-   2-chloro-4-nitro-benzene-diazonium 2-naphthalenesulfonate;-   2,5-diethoxy-4-[(4-methylphenyl)sulfanyl]benzenediazonium salt;-   Fast Blue B salt;-   9H-fluorene-2-diazonium salt;-   9,10-dioxo-9,10-dihydro-1-anthracenediazonium salt; and-   2-Methoxy-4-morpholinobenzenediazonium salt.

In a further embodiment, the electroactive diaryliodonium derivative isa compound of the following formula:

Wherein

X is an inorganic or organic anion selected from the group consisting ofanion of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻, PF₆, HgBr₂,HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate;

Y is a 5-7 membered saturated cyclic or heterocyclic, aromatic orheteroaromatic ring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group; and

Z is a 5-7 membered saturated cyclic or heterocyclic, aromatic orheteroaromatic ring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

In specific embodiments, the electroactive diaryliodonium derivative canbe selected from the list of:

-   Diphenyliodonium iodide salt;-   bis(4-methoxyphenyl)iodonium salt;-   bis(4-methylphenyl)iodonium salt;-   bis(4-tert-butylphenyl)iodonium salt;-   4-(phenyliodonio)benzoate salt;-   bis(4-fluorophenyl)iodonium salt;-   bis(4-bromophenyl)iodonium salt;-   bis(4-tert-butylphenyl)iodonium salt;-   mesityl(4-methylphenyl)iodonium salt;-   2-(phenyliodonio)benzoate salt;-   2-(phenyliodonio)benzoate;-   (4-nitrophenyl)(phenyl)iodonium;-   phenyl[3-(trifluoromethyl)phenyl]iodonium salt;-   (3-bromophenyl)(mesityl)iodonium salt;-   (2-bromophenyl)(mesityl)iodonium salt;-   mesityl[3-(trifluoromethyl)phenyl]iodonium salt;-   mesityl(4-nitrophenyl)iodonium salt;-   Diphenyleneiodonium salt; and-   3,7-dinitrodibenziodolium salt.

In a further embodiment, the electroactive arylsulfonium derivative is acompound of the following formula:

Wherein

X is an inorganic or organic anion selected from the group consisting ofanion of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻, PF₆, HgBr₂,HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate;

Y is a bond, C₁-C₈ straight-chain or branched alkyl group, or 5-7membered saturated cyclic or heterocyclic, aromatic or heteroaromaticring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

Z is a bond, C₁-C₈ straight-chain or branched alkyl group, or 5-7membered saturated cyclic or heterocyclic, aromatic or heteroaromaticring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group; and

W is a bond, C₁-C₈ straight-chain or branched alkyl group, or 5-7membered saturated cyclic or heterocyclic, aromatic or heteroaromaticring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

wherein at least two of W, Y and Z are not a bond, C₁-C₈ straight-chainor branched alkyl group.

In specific embodiments, the electroactive arylsulfonium derivative canbe selected from the list of:

-   Triphenylsulfonium salt;-   diphenyl[4-(phenylsulfanyl)phenyl] sulfonium salt;-   (4-fluorophenyl)(diphenyl)sulfonium salt;-   tris(4-tert-butylphenyl)sulfonium salt;-   tris(4-chlorophenyl)sulfonium salt;-   (4-chlorophenyl)diphenylsulfonium salt;-   tri-p-tolylsulfonium salt;-   tris(4-methoxyphenyl)sulfonium salt;-   (4-methoxyphenyl)diphenylsulfonium salt;-   ethyl(4-methoxyphenyl)(phenyl)sulfonium salt;-   (3-chloropropyl)diphenylsulfonium salt; and-   (5-chloropentyl)diphenylsulfonium salt.

In another embodiment, an electroactive bioadhesive compositioncomprises the electroactive polymer of the present invention andsuitable solvents, surfactants, stabilizers, fillers and otheradditives. The additives may be anti-inflammatory drugs, anti-proteases,antibiotics, and/or anti-restenosis compounds.

In yet further embodiment, the composition can be in a form of hydrogel,biocompatible film, patch or bondage. In addition, the composition maycontain conductive particles or polymers of size less than 50 micronmade of gold, iron, iron oxides, platinum, magnesium, graphene, carbonblack, carbon nanotubes, polyacetylene, poly(3-alkyl-thiophene),polyaniline, polyisothianaphthalene, poly-(p-phenylene),poly-(p-phenylene vinylene), polypyrole, polythiophene, or combinationsthereof. The composition is electrically conductive with conductivitygreater than 0.01 siemen per centimeter.

In additional embodiment, the conductive particles can be coated withanionic or cationic coating comprising fatty acids, silica, polyethyleneglycol, pluronics, poloxamers, polydopamine, polylysine or any suitablepeptide.

In a general embodiment, the composition may be used in surgery, such asgastrointestinal surgery towards cancer removal, anastomoses procedures,such as blood vessel anastomoses wherein two tubes or lumens must bejoined, tissue fixation, suture sealing and replacement, treatment oflung punctures, body lumen punctures or leaks, cerebrospinal fluidmembrane damages, obesity treatments, and bowel obstructions.

In still another embodiment, a method for the preparation of theelectroactive polymer of the present invention comprises the steps of:

-   -   (a) Preparing a solution of said biocompatible polymer having        concentration of 0.1 to 100 mg/ml at pH 7.2;    -   (b) Dissolving said electroactive derivatives of diazonium,        arylsulfonium, or diaryliodonium compound in a suitable organic        solvent within the concentration range of 0.01 to 100 mM;    -   (c) Mixing and reacting the solution of said biocompatible        polymer prepared in a) with the solution of the electroactive        derivative prepared in b), in order to covalently attach the        electroactive groups to the polymer strand; that is in the form        of a thin film on a conductive material, i.e. the electrode.    -   (d) Purifying said polymer modified in c) on a Sephadex G-25        column or using other conventional purification and separation        techniques in order to remove the unbound electroactive        derivative molecules.

In yet another embodiment, method of tissue fixation comprises the stepsof:

-   -   (a) Applying the electroactive bioadhesive composition of the        present invention, being a hydrogel, film, patch or bondage, to        a tissue to be fixed; and    -   (b) Applying a voltage potential to an electrode on which the        electroactive polymer is placed, across the composition and        tissue area with negative 10 to positive 10 Volts vs. a        reference electrode that can be of any type such as Ag/AgCl or        Ag wire or any other electrode that has a constant potential,        which depends on the composition, in an electrolyte with a        concentration of between 0.01 and 1 M.

In still further embodiment, voltage potential is between negative 5 topositive 5 Volts, such as negative 2 to positive 2 Volts, and time ofvoltage potential in both cases is less than 20 minutes. The potentialcan be applied also in a sweeping mode, i.e., by changing the potentialunder a fixed or changeable scan rate (in mV/s) and scanning one orseveral cycles.

Various embodiments of the invention may allow various benefits, and maybe used in conjunction with various applications. The details of one ormore embodiments are set forth in the accompanying figures and thedescription below. Other features, objects and advantages of thedescribed techniques will be apparent from the description and drawingsand from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be understood and appreciated more fully fromthe following detailed description taken in conjunction with theappended figures. Various exemplary embodiments are well illustrated inthe accompanying figures with the intent that these examples not berestrictive. It will be appreciated that for simplicity and clarity ofthe illustration, elements shown in the figures referenced below areschematic. Of the accompanying figures:

FIG. 1 is a synthetic route to thin films crosslinked with diazonium,arylsulfonium, or diaryliodonium derivatives used in the tissuefixation;

FIG. 2 is a schematic of electroactivated tissue fixation throughdiazonium, arylsulfonium, or diaryliodonium derivatives surfacefunctionalization;

FIG. 3 shows free radicals on surfaces react with nearly any polypeptidechain nearby, instantly creating new covalent bonds. As an example, byapplying high surface concentrations of free radicals on PLGA thinfilms, strong bioadhesion was observed onto soft arterial tissue.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, various aspects of the invention will bedescribed. For purposes of explanation, specific, configurations anddetails are set forth in order to provide a thorough understanding ofthe invention. However, it will also be apparent to one skilled in theart that the invention may be practiced without the specific detailspresented herein. Furthermore, well-known features may be omitted orsimplified in order not to obscure the invention.

It should be noted that although a portion of the discussion may relateto electroactive bioadhesive materials, compositions and methods, thepresent invention is not limited in this regard, and embodiments of thepresent invention may be used in conjunction with various otherbiomaterials, compositions and methods of treatment. As such, someembodiments of the invention may be used, for example, in conjunctionwith use of various biocompatible films, patches or bondages and invarious surgery procedures. Some embodiments of the invention may beused not necessarily in the context of in vivo treatment.

“Biocompatible” material is defined as a natural or synthetic materialhaving low variability, high purity, and no detectable biologicalreactivity as determined by biocompatibility tests. “Biocompatiblepolymer” is a natural or synthetic polymer having low variability, highpurity, and no detectable biological reactivity as determined bybiocompatibility tests. “Bioadhesive” or “bioadhesive material” means asynthetic material designed to adhere to biological tissues. Bydefinition, bioadhesives are biocompatible materials.

A biocompatible polymer of the invention is built from a single strandof repeating units and up to 5,000 electroactive groups covalentlyattached to said strand, and it has a molecular weight of up to 3million Daltons. The crosslinked electroactive groups are derivatives ofdiazonium, arylsulfonium, diaryliodonium or combinations thereof.Arylsulfonium in present context may refer to mono-, di- ortri-arylsulfonium, for example, triphenylsulfonium, diphenylsulfonium,or alkyldiphenylsulfonium.

The main polymeric strand or backbone can be any bioresorbable polymerthat has been FDA-approved as a medical device selected from the groupconsisting of polyethylene glycol (PEG), PEG fatty acid esters,poly-L-lactic acid (PLLA), poly(lactide-co-glycolide) (PLGA), polycaprolactone (PCL), polyvinyl pyrrolidone (PVP), polyvinyl alcohol(PVA), collagen, chitosan, hydroxy propyl cellulose, polyamides,polyglycerol esters of fatty acids, polysaccharides, polyesters, andcombinations thereof. The polysaccharide may be selected from the groupconsisting of dextran, chitosan, heparin, hyaluronic acid, alginates,starch, glycogen, amylose, amylopectin, cellulose, xylan, and numerousother natural and synthetic polysaccharides.

The specific example of a biocompatible polymer that has beenFDA-approved as a medical device is poly(lactic-co-glycolic acid) (PLGA)employed in a form of a thin film matrix. It has been incorporated intoa number of drug delivery medical devices due to its numerousadvantages, i.e. commercial availability in a range of formulations andcontrolled release for numerous therapeutics. The PLGA polymer can beblended for independent tailoring of thin film mechanical properties tomatch soft tissue, controlled drug release, and conductivity.

In a further embodiment, the electroactive diazonium derivative is acompound of the following formula:

wherein

X is an inorganic or organic anion selected from the group consisting ofanion of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻, PF₆, HgBr₂,HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate;

R is a bond or 5-7 membered saturated cyclic or heterocyclic, aromaticor heteroaromatic ring unsubstituted or mono-, di- or tri-substitutedwith:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

Y is a bond or saturated and unsaturated C₁-C₅₀₀ straight-chain orbranched alkyl, alkenyl or alkynyl group, wherein said chain mayoptionally incorporate at least one hetero atom, and may also compriseat least one substituent; and

Z is any suitable functional group, such as halogen, amino, cyano,hydroxy, aldehyde, alkoxycarbonyl, N-amide, N-hydroxysuccinimide ester,maleimide or thiol.

In specific embodiments, the electroactive diazonium derivative can beselected from the list of:

-   4-(dimethylamino)-benzene-diazonium salt;-   2-chloro-benzene-diazonium salt;-   1-naphthalene-diazonium salt;-   4-anilino-benzene-diazonium salt;-   3,5-dichloro-benzene-diazonium salt;-   1-pyrene-diazonium salt;-   4-Methoxy-benzene-diazonium salt;-   4-bromo-benzene-diazonium salt;-   4-formyl-benzene-diazonium salt;-   4-Nitro-benzene-diazonium salt;-   Fast Red TR salt;-   Variamine blue B salt;-   4-[ethyl(2-hydroxyethyl)amino]-benzene-diazonium salt;-   4-(diethylamino)-2-methyl-benzene-diazonium salt;-   4-(ethylamino)-3-methyl-benzene-diazonium salt;-   5-chloro-2-methoxy-benzene-diazonium salt;-   3-methyl-4-nitro-benzene-diazonium salt;-   bis[4-(diethylamino)-2-methyl-benzene-diazonium] salt;-   2,4-dichloro-benzene-diazonium salt;-   2-methoxy-4-nitro-benzene-diazonium salt;-   2-chloro-4-nitro-benzene-diazonium 2-naphthalenesulfonate;-   2,5-diethoxy-4-[(4-methylphenyl)sulfanyl]benzenediazonium salt;-   Fast Blue B salt;-   9H-fluorene-2-diazonium salt;-   9,10-dioxo-9,10-dihydro-1-anthracenediazonium salt; and-   2-Methoxy-4-morpholinobenzenediazonium salt.

In a further embodiment, the electroactive diaryliodonium derivative isa compound of the following formula:

Wherein

X is an inorganic or organic anion selected from the group consisting ofanion of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻, PF₆, HgBr₂,HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate;

Y is a 5-7 membered saturated cyclic or heterocyclic, aromatic orheteroaromatic ring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

Z is a 5-7 membered saturated cyclic or heterocyclic, aromatic orheteroaromatic ring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group.

In specific embodiments, the electroactive diaryliodonium derivative canbe selected from the list of:

-   Diphenyliodonium iodide salt;-   bis(4-methoxyphenyl)iodonium salt;-   bis(4-methylphenyl)iodonium salt;-   bis(4-tert-butylphenyl)iodonium salt;-   4-(phenyliodonio)benzoate salt;-   bis(4-fluorophenyl)iodonium salt;-   bis(4-bromophenyl)iodonium salt;-   bis(4-tert-butylphenyl)iodonium salt;-   mesityl(4-methylphenyl)iodonium salt;-   2-(phenyliodonio)benzoate salt;-   2-(phenyliodonio)benzoate;-   (4-nitrophenyl)(phenyl)iodonium;-   phenyl[3-(trifluoromethyl)phenyl]iodonium salt;-   (3-bromophenyl)(mesityl)iodonium salt;-   (2-bromophenyl)(mesityl)iodonium salt;-   mesityl[3-(trifluoromethyl)phenyl]iodonium salt;-   mesityl(4-nitrophenyl)iodonium salt;-   Diphenyleneiodonium salt; and-   3,7-dinitrodibenziodolium salt.

In a further embodiment, the electroactive arylsulfonium derivative is acompound of the following formula:

Wherein

X is an inorganic or organic anion selected from the group consisting ofanion of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻, PF₆, HgBr₂,HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate;

Y is a bond, C₁-C₈ straight-chain or branched alkyl group, or 5-7membered saturated cyclic or heterocyclic, aromatic or heteroaromaticring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

Z is a bond, C₁-C₈ straight-chain or branched alkyl group, or 5-7membered saturated cyclic or heterocyclic, aromatic or heteroaromaticring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl-group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

W is a bond, C₁-C₈ straight-chain or branched alkyl group, or 5-7membered saturated cyclic or heterocyclic, aromatic or heteroaromaticring unsubstituted or mono-, di- or tri-substituted with:

C₁-C₈ straight-chain or branched alkyl group, C₂-C₈ straight-chain orbranched alkenyl or alkynyl group, or phenyl group substituted at anyring position with one or more the same or different C₁-C₈straight-chain or branched alkyl group, phenyl or heterocyclic ring,which may be optionally substituted with one or more the same ordifferent C₁-C₈ straight-chain or branched alkyl group, C₁-C₈ alkoxygroup, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxyl group, nitrogroup, halogen atom or amino group optionally mono or di-substitutedwith the same or different C₁-C₈ straight-chain or branched alkyl group;

methyl group substituted with 1-3 halogen atoms;

amino group optionally mono or di-substituted with the same or differentC₁-C₈ straight-chain or branched alkyl group;

thiol or thioether group having the same or different C₁-C₈straight-chain or branched alkyl group;

sulfone or sulfate group having the same or different C₁-C₈straight-chain or branched alkyl group;

nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonic acid group;or

alkoxy or alkoxycarbonyl group having the same or different C₁-C₈straight-chain or branched alkyl group;

wherein at least two of W, Y and Z are not a bond, C₁-C₈ straight-chainor branched alkyl group.

In specific embodiments, the electroactive arylsulfonium derivative canbe selected from the list of:

-   Triphenylsulfonium salt;-   diphenyl[4-(phenylsulfanyl)phenyl]sulfonium salt;-   (4-fluorophenyl)(diphenyl)sulfonium salt;-   tris(4-tert-butylphenyl)sulfonium salt;-   tris(4-chlorophenyl)sulfonium salt;-   (4-chlorophenyl)diphenylsulfonium salt;-   tri-p-tolylsulfonium salt;-   tris(4-methoxyphenyl)sulfonium salt;-   (4-methoxyphenyl)diphenylsulfonium salt;-   ethyl(4-methoxyphenyl)(phenyl)sulfonium salt;-   (3-chloropropyl)diphenylsulfonium salt; and-   (5-chloropentyl)diphenylsulfonium salt.

Reference is now made to FIG. 1 schematically showing synthetic route tothe biocompatible polymer crosslinked with diazonium, arylsulfonium,diaryliodonium or combinations thereof.

Reference is now made to FIG. 2 where the biocompatible polymercrosslinked with derivatives of diazonium, arylsulfonium, diaryliodoniumor combinations thereof is followed by electro-activation through theelectrochemical reduction or oxidation, and soft tissue fixation. Onceactivated with a voltage potential, for instance at ±5 Volts or byscanning the potential with a fixed or changeable scan rate, freeradicals are formed that instantly react and crosslink soft tissues andbiomaterials by C—C bond formation.

The novel electroactive polymer used for bioadhesion was conceived afterincorporating of key advances in the fields of plasma surfacemodification, biocompatible polymer functionalized with diazonium,arylsulfonium, diaryliodonium electrochemistry, and antibody-basedavidity binding concepts. This polymer allows one to trigger the tissueadhesion in situ, directly at the time and place the tissue fixation isrequired. The free-radical bond formation employed is advantageous overother known covalent protein bonding methods, as it leaves the bulkprotein conformation relatively intact.

Current commercial bioadhesives employ adhesive mechanisms that arerelatively inflexible and tend to have narrow applications. Thebiocompatible polymer of the present invention, based onelectro-activation of diazonium, arylsulfonium, or diaryliodoniumresidues, offers greater flexibility by allowing on-demand activation ofthe diazonium, arylsulfonium, or diaryliodonium-based surface binding.It is the only electroactivated bioadhesive that is free of monomers andtoxic photo-initiators. This electroactive polymer creates a fundamentalshift in bioadhesive technology that would have considerable impact onmedical implants—in vivo adhesion is a difficult hurdle that has yet tobe overcome—especially in wet and protein-filled environments.

Treatment of surfaces by non-thermal plasmas is well known to createfree radicals on biomaterial surfaces while leaving the bulk unaffected.The highly reactive nature of free radicals causes them to have a shorthalf-life, on the order of milliseconds to seconds. However, even withinthis short life, free radicals react with nearly any polypeptide chainsnearby, instantly creating new covalent bonds. As an, example, byapplying high surface concentrations of free radicals on PLGA thinfilms, strong bioadhesion was observed onto soft arterial tissue, asseen in FIG. 3.

Free radicals are generally considered detrimental due to theirimplications in cellular aging. Recently however, several laboratorieshave revealed that proteins covalently immobilized by free radicalmechanisms tend to retain protein conformation and have morefunctionality. This is a key observation in the design for soft tissuebioadhesives—the higher the protein conformation retained, the lower thelocal tissue toxicity and inflammation is likely to be.

Although bioadhesives based on free radical covalent bonding areinteresting, the plasma generation method is impractical due to thecomplexity of the plasma ovens and the short term half-lives of theradicals themselves (the majority are likely to be quenched uponatmospheric exposure). In order to take advantage of the free radicalcovalent bonding, a mechanism is needed to generate the radicals in situ(specifically at the time and place soft tissue bonding is desired). Thefollowing unique functional groups-diazonium, arylsulfonium,diaryliodonium—allows in situ formation of free radical by an appliedvoltage potential.

Reference is now made to FIG. 2, which shows on-demand,electro-activated surface adhesion through surface functionalization ofdiazonium, arylsulfonium, or diaryliodonium derivatives. The surface ofPLGA thin films undergo plasma activated ammonia reactions, leaving anamine-functionalized surface that readily reacts with brominederivatives of diazonium, arylsulfonium, or diaryliodonium compound.Upon an applied voltage potential, the diazonium, arylsulfonium, ordiaryliodonium compounds decompose to an extremely reactive freeradical. The free radical instantly crosslinks with any nearbypolypeptide chains of soft tissues—a fact that has made it widelypopular for protein surface functionalization.

The electroactive functional groups allow in situ free radicalgeneration with little to no toxic byproducts for relatively harmlessprotein backbone covalent bonding. Many other event activated freeradical forming are available, i.e. photoactive compounds such asazides, diazo compounds, benzophenone, anthraquinone, diaryldiazomethanes, and psoralene. However, the UV irradiation is requiredfor photoactivation—the large intensities of ionizing radiation requiredfor photo-activation can cause harm to the adjacent tissues.

The electroactive mechanism of adhesion has many advantages over otheradhesion mechanisms. For example, cyanoacrylate cannot be activated ondemand, often begins to polymerize at the slightest amount of moisture,and tends to be toxic after degradation. Light activated acrylate orepoxide polymerization based bioadhesives tend to have high fronttemperatures (causing thermal damage) and leave behind toxic monomersby-products, as well as photoinitiators. The diazonium functional groupleaves no monomer or photoinitiator by-products after curing.

With the use of commercially available diazonium and diaryliodoniumderivatives, novel poly-diazoniums and poly-diaryliodoniums can beeasily synthesized by employing antibody inspired avidity-type bindingmechanisms in a one-pot synthesis.

“Avidity” is a term to define the combined strength of multiple bondinginteractions simultaneously with one or more targets. Poly-diazoniumsand poly-diaryliodoniums bioadhesion attempts to avidity bond softtissue to soft tissue or soft tissue to other relevant biomaterials. Thepoly-diazonium and poly-diaryliodonium based bioadhesive could betailored via numerous methods, depending on the application. Forexample, interfacial bioadhesion strength could be adjusted by varyingthe density of the functional groups on the polymer backbone or bycontrolling the intensity/time of the applied voltage potential, so onlythe needed fraction of diazonium or diaryliodoniums are activated intofree-radicals.

In light of the above, the biocompatible polymer of the invention hasthe following advantages over commercially available bioadhesives, suchas cyanoacrylates and fibrin-based bioadhesives:

-   -   Can stick to wet or dry materials;    -   Activated on demand with immediate electro-curing;    -   Adapted to existing biomaterials that have been FDA-approved as        a medical device;    -   Adhesion mechanism leaves protein in tissues relatively intact;    -   Avoids any toxic photoinitiators;    -   Degradation has no toxic by-products; and    -   Multiple functional groups can be easily converted in the        reactive diazonium, triarylsulfonium, alkyldiphenylsulfonium, or        diaryliodonium derivatives, including primary and secondary        amines, ketones; and aldehydes.

The electroactive bioadhesive composition may further comprise theelectroactive polymer of the present invention and suitable solvents,surfactants, stabilizers, fillers and other additives. The additives maybe anti-inflammatory drugs, anti-proteases, antibiotics, and/oranti-restenosis compounds. The composition can be in a form of hydrogel,biocompatible film, patch or bandage.

Bioadhesive hydrogels could have multiple uses in surgeries,particularly in anastomosis procedures, where two tubes or lumens mustbe joined. For example, gastrointestinal surgeries towards cancerremoval, obesity treatments, and bowel obstructions. Blood vesselanastomosis is in significant need of new bioadhesives. Suturescurrently limit blood vessel anastomosis to vessels of more than 1 mm indiameter, which limits reattachment of amputated limbs.

The bioadhesive hydrogels can be prepared from many common biocompatiblepolymers and polyglycans, for example dextran, chitosan, heparin,hyaluronic acid, alginates, starch, glycogen, amylose, amylopectin,cellulose, xylan, and numerous other natural and syntheticpolysaccharides. Polysaccharides can be functionalized with diazonium,arylsulfonium, or diaryliodonium derivatives through primary andsecondary amines groups, carbonyl groups such as aldehyde groups,ketones, and carboxylic acids. Most preferably are the primary aminesand aldehyde groups. Most polysaccharides can be turned intopoly-aldehydes through oxidation reactions such as treatment with sodiumperiodate, treatment with nitrous acid, etc.

Bioadhesive thin films have numerous applications across the medicalspectrum. Biodegradable thin films of the present invention offer a morecost effective replacement for sutures, band aids, or dressings. Drugimpregnated with diazonium, arylsulfonium, or diaryliodoniumderivatives—based bioadhesives offer local drug delivery to a variety ofsoft-tissues, thereby eliminating systemic drug side effects andfirst-pass liver metabolism, while allowing delivery of acid-labiletherapeutics (which cannot be taken orally). The novel approach inherentin the diazonium, arylsulfonium, diaryliodonium derivatives—basedbioadhesive design allows adhesion even in wet, protein filledenvironments—a claim no other bioadhesive has yet to make. This allowstargeting of the vasculature ailments by piggybacking the bioadhesivethin films of the invention on modified angioplasty balloon catheters.

In addition, the composition can be in a form of hydrogel, biocompatiblefilm, patch or bondage. In addition, the composition may containconductive particles or polymers of size less than 50 micron made ofgold, iron, iron oxides, platinum, magnesium, graphene, carbon black,carbon nanotubes, polyacetylene, poly(3-alkyl-thiophene), polyaniline,polyisothianaphthalene, poly-(p-phenylene), poly-(p-phenylene vinylene),polypyrole, polythiophene, or combinations thereof. The composition iselectrically conductive with conductivity greater than 0.01 siemen percentimeter.

In additional embodiment, the conductive particles can be coated withanionic or cationic coating comprising fatty acids, silica, polyethyleneglycol, pluronics, poloxamers, polydopamine, polylysine or any suitablepeptide.

Bioadhesives towards organ sealants or vascular tissues is thepreferable application, due to the plethora of sealants needed, ease ofreach with common catheters, or both (sealants for air/lung or duramater/fluid leakages, trauma haemostasis, or intestinal anastomoses).

According to the embodiments of the invention, the composition may beused in surgery, such as gastrointestinal surgery towards cancerremoval, anastomoses procedures, such as blood vessel anastomoseswherein two tubes or lumens must be joined, tissue fixation, suturesealing and replacement, treatment of lung punctures, body lumenpunctures or leaks, cerebrospinal fluid membrane damages, obesitytreatments, and bowel obstructions.

A method for the preparation of the electroactive polymer of the presentinvention involves the following steps:

-   -   (a) Preparing a solution of said biocompatible polymer having        concentration of 0.1 to 100 mg/ml at pH 7.2;    -   (b) Dissolving said diazonium, arylsulfonium, or diaryliodonium        derivative compound in a suitable organic solvent within the        concentration range of 0.01 to 100 mM;    -   (c) Mixing and reacting the solution of said biocompatible        polymer prepared in a) with the solution of the derivative        prepared in b), in order to covalently attach the derivatives        groups to the polymer strand; that is in the form of a thin film        on a conductive material, i.e. the electrode.    -   (d) Purifying said polymer modified in c) on a Sephadex G-25        column or using other conventional, purification and separation        techniques in order to remove the unbound derivative molecules.

According to another embodiment of the invention, method of tissuefixation comprises the following steps:

-   -   (a) Applying the electroactive bioadhesive composition of the        present invention, being a hydrogel, film, patch or bondage, to        a tissue to be fixed; and    -   (b) Applying a voltage potential to an electrode on which the        electroactive polymer is placed, across the composition and        tissue area with negative 10 to positive 10 Volts vs. a        reference electrode that can be of any type such as Ag/AgCl or        Ag wire or any other electrode that has a constant potential,        which depends on the composition, in an electrolyte having a        concentration of between 0.01 and 1 M.

The applied potential voltage range of the electro-activation is betweennegative 10 Volts and positive 10 Volts, preferably between negative 5and positive 5 Volts, and most preferably negative 2 Volts and positive2 Volts and time of potential voltage in both cases is less than 20minutes. The application of potential can be in the form of a constantor variable potential including AC.

Although portions of the discussion herein may relate to bioadhesion,the present invention is not limited in this regard, and may include,for example, additional surgical procedures.

A biocompatible polymer, composition and methods in accordance with someembodiments of the invention may be used, for example, in conjunctionwith a device which may be inserted into a human body. However, thescope of the present invention is not limited in this regard. Forexample, some embodiments of the invention may be used in conjunctionwith a device which may be inserted into a non-human body or an animalbody.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

The invention claimed is:
 1. An electroactive biocompatible polymercomprising a biocompatible polymer comprising a single strand ofrepeating units and up to 5,000 electroactive groups covalently attachedto said strand, wherein precursors of said electroactive groups areselected from the group consisting of a diazonium derivative, anarylsulfonium derivative, a diaryliodonium derivative, and combinationsthereof; wherein the biocompatible polymer is selected from the groupconsisting of poly-L-lactic acid (PLLA), poly(lactide-co-glycolide)(PLGA), poly caprolactone (PCL), polyvinyl pyrrolidone (PVP), polyvinylalcohol (PVA), collagen, hydroxy propyl cellulose, polyglycerol estersof fatty acids, polysaccharides, and combinations thereof.
 2. Theelectroactive biocompatible polymer according to claim 1, wherein thepolysaccharides are selected from the group consisting of dextran,chitosan, heparin, hyaluronic acid, alginates, starch, glycogen,amylose, amylopectin, cellulose, and xylan.
 3. The electroactivebiocompatible polymer according to claim 1, wherein said diazoniumderivative is a compound of the following formula:

wherein X is an inorganic or organic anion selected from the groupconsisting of anions of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻,PF₆, HgBr₂, HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate; R is a bond, 5-7 membered saturated cyclic ring,5-7 membered heterocyclic ring, 5-7 membered aromatic ring or 5-7membered heteroaromatic ring, each of which is unsubstituted, mono-, di-or tri-substituted with: C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₂-C₈ straight-chain alkenyl group, C₃-C₈branched-chain alkenyl group, C₂-C₈ straight-chain alkynyl group, C₃-C₈branched-chain alkynyl group, or phenyl group substituted at any ringposition with one or more the same or a different C₁-C₈ straight-chainalkyl group, C₃-C₈ branched-chain alkyl group, phenyl ring orheterocyclic ring, each of which is optionally substituted with one ormore the same or a different C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₁-C₈ alkoxy group, C₁-C₈ alkoxycarbonylgroup, carboxyl group, hydroxyl group, nitro group, halogen atom oramino group, each of which is optionally mono or di-substituted with thesame or a different C₁-C₈ straight-chain alkyl group or C₃-C₈branched-chain alkyl group; methyl group substituted with 1-3 halogenatoms; amino group optionally mono or di-substituted with the same or adifferent C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chain alkylgroup; thiol or thioether group having the same or different C₁-C₈straight-chain alkyl group or C₃-C₈ branched-chain alkyl group; sulfoneor sulfate group having the same or a different C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; nitro, cyano, halogen,hydroxy, carboxylic acid or sulfonic acid group; or alkoxy oralkoxycarbonyl group having the same or different a C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; Y is a bond, saturatedC₁-C₅₀₀ straight-chain alkyl group, C₃-C₅₀₀ branched-chain alkyl group,unsaturated C₂-C₅₀₀ straight-chain alkyl group, unsaturated C₃-C₅₀₀branched-chain alkyl group, alkenyl group or alkynyl group, wherein anyof said C₁-C₅₀₀ straight-chain alkyl group, C₃-C₅₀₀ branched-chain alkylgroup, alkenyl group or alkynyl group optionally incorporates at leastone hetero atom, and wherein any of said C₁-C₅₀₀ straight-chain alkylgroup, C₃-C₅₀₀ branched-chain alkyl group, unsaturated C₂-C₅₀₀straight-chain alkyl group, unsaturated C₃-C₅₀₀ branched-chain alkylgroup, alkenyl group or alkynyl group optionally comprises at least onesubstituent; and Z is any suitable functional group selected from thegroup consisting of halogen, amino, cyano, hydroxy, aldehyde,alkoxycarbonyl, N-amide, N-hydroxysuccinimide ester, maleimide, andthiol.
 4. The electroactive biocompatible polymer according to claim 3,wherein said diazonium derivative is 4-(dimethylamino)-benzene-diazoniumsalt; 2-chloro-benzene-diazonium salt; 1-naphthalene-diazonium salt;4-anilino-benzene-diazonium salt; 3,5-dichloro-benzene-diazonium salt;1-pyrene-diazonium salt; 4-methoxy-benzene-diazonium salt;4-bromo-benzene-diazonium salt; 4-formyl-benzene-diazonium salt;4-nitro-benzene-diazonium salt; Fast Red TR salt; Variamine blue B salt;4-[ethyl(2-hydroxyethyl)amino]-benzene-diazonium salt;4-(diethylamino)-2-methyl-benzene-diazonium salt;4-(ethylamino)-3-methyl-benzene-diazonium salt;5-chloro-2-methoxy-benzene-diazonium salt;3-methyl-4-nitro-benzene-diazonium salt;bis[4-(diethylamino)-2-methyl-benzene-diazonium] salt;2,4-dichloro-benzene-diazonium salt; 2-methoxy-4-nitro-benzene-diazoniumsalt; 2-chloro-4-nitro-benzene-diazonium 2-naphthalenesulfonate salt;2,5-diethoxy-4-[(4-methylphenyl)sulfanyl]benzenediazonium salt; FastBlue B salt; 9H-fluorene-2-diazonium salt;9,10-dioxo-9,10-dihydro-1-anthracenediazonium salt; or2-methoxy-4-morpholinobenzenediazonium salt.
 5. The electroactivebiocompatible polymer according to claim 1, wherein said diaryliodoniumderivative is a compound of the following formula:

wherein X is an inorganic or organic anion selected from the groupconsisting of anions of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻,PF₆, HgBr₂, HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate; Y is a 5-7 membered saturated cyclic ring, 5-7membered heterocyclic ring, 5-7 membered aromatic ring or 5-7 memberedheteroaromatic ring, each of which is unsubstituted, mono-, di- ortri-substituted with: C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₂-C₈ straight-chain alkenyl group, C₃-C₈branched-chain alkenyl group, C₂-C₈ straight-chain alkynyl group, C₃-C₈branched-chain alkynyl group, or phenyl group substituted at any ringposition with one or more the same or a different C₁-C₈ straight-chainalkyl group, C₃-C₈ branched-chain alkyl group, phenyl ring orheterocyclic ring, each of which is optionally substituted with one ormore the same or a different C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₁-C₈ alkoxy group, C₁-C₈ alkoxycarbonylgroup, carboxyl group, hydroxyl group, nitro group, halogen atom oramino group, each of which is optionally mono or di-substituted with thesame or a different C₁-C₈ straight-chain alkyl group or C₃-C₈branched-chain alkyl group; methyl group substituted with 1-3 halogenatoms; amino group optionally mono or di-substituted with the same or adifferent C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chain alkylgroup; thiol or thioether group having the same or different C₁-C₈straight-chain alkyl group or C₃-C₈ branched-chain alkyl group; sulfoneor sulfate group having the same or a different C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; nitro, cyano, halogen,hydroxy, carboxylic acid or sulfonic acid group; or alkoxy oralkoxycarbonyl group having the same or different a C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; Z is a 5-7 memberedsaturated cyclic ring, 5-7 membered heterocyclic ring, 5-7 memberedaromatic ring or 5-7 membered heteroaromatic ring, each of which isunsubstituted, mono-, di- or tri-substituted with: C₁-C₈ straight-chainalkyl group, C₃-C₈ branched-chain alkyl group, C₂-C₈ straight-chainalkenyl group, C₃-C₈ branched-chain alkenyl group, alkynyl group, orphenyl group substituted at any ring position with one or more the sameor a different C₁-C₈ straight-chain alkyl group, C₃-C₈ branched-chainalkyl group, phenyl ring or heterocyclic ring, each of which isoptionally substituted with one or more the same or a different C₁-C₈straight-chain alkyl group, C₃-C₈ branched-chain alkyl group, C₁-C₈alkoxy group, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxylgroup, nitro group, halogen atom or amino group, each of which isoptionally mono or di-substituted with the same or a different C₁-C₈straight-chain alkyl group or C₃-C₈ branched-chain alkyl group; methylgroup substituted with 1-3 halogen atoms; amino group optionally mono ordi-substituted with the same or a different C₁-C₈ straight-chain alkylgroup or C₃-C₈ branched-chain alkyl group; thiol or thioether grouphaving the same or different C₁-C₈ straight-chain alkyl group or C₃-C₈branched-chain alkyl group; sulfone or sulfate group having the same ora different C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chainalkyl group; nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonicacid group; or alkoxy or alkoxycarbonyl group having the same ordifferent a C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chainalkyl group.
 6. The electroactive biocompatible polymer according toclaim 5, wherein said diaryliodonium derivative is diphenyliodoniumiodide salt; bis(4-methoxyphenyl)iodonium salt;bis(4-methylphenyl)iodonium salt; bis(4-tert-butylphenyl)iodonium salt;4-(phenyliodonio)benzoate salt; bis(4-fluorophenyl)iodonium salt;bis(4-bromophenyl)iodonium salt; bis(4-tert-butylphenyl)iodonium salt;mesityl(4-methylphenyl)iodonium salt; 2-(phenyliodonio)benzoate salt;2-(phenyliodonio)benzoate; (4-nitrophenyl)(phenyl)iodonium;phenyl[3-(trifluoromethyl)phenyl]iodonium salt;(3-bromophenyl)(mesityl)iodonium salt; (2-bromophenyl)(mesityl)iodoniumsalt; mesityl[3-(trifluoromethyl)phenyl]iodonium salt;mesityl(4-nitrophenyl)iodonium salt; diphenyleneiodonium salt; or3,7-dinitrodibenziodolium salt.
 7. The electroactive biocompatiblepolymer according to claim 1, wherein said arylsulfonium derivative is acompound of the following formula:

wherein X is an inorganic or organic anion selected from the groupconsisting of anions of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, BF₃, ZnCl₂, HSO₄ ⁻,PF₆, HgBr₂, HgBr₂Cl₂, NO₃ ⁻, nonafluoro-1-butanesulfonate,trifluoromethanesulfonate, dimethoxy-2-anthracenesulfonate, andmethylbenzenesulfonate; Y is a bond, C₁-C₈ straight-chain alkyl group,C₃-C₈ branched-chain alkyl group, 5-7 membered saturated cyclic ring,5-7 membered heterocyclic ring, 5-7 membered aromatic ring or 5-7membered heteroaromatic ring, each of which is unsubstituted, mono-, di-or tri-substituted with: C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₂-C₈ straight-chain alkenyl group, C₃-C₈branched-chain alkenyl group, C₂-C₈ straight-chain alkynyl group, C₃-C₈branched-chain alkynyl group, or phenyl group substituted at any ringposition with one or more the same or a different C₁-C₈ straight-chainalkyl group, C₃-C₈ branched-chain alkyl group, phenyl ring orheterocyclic ring, each of which is optionally substituted with one ormore the same or a different C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₁-C₈ alkoxy group, C₁-C₈ alkoxycarbonylgroup, carboxyl group, hydroxyl group, nitro group, halogen atom oramino group, each of which is optionally mono or di-substituted with thesame or a different C₁-C₈ straight-chain alkyl group or C₃-C₈branched-chain alkyl group; methyl group substituted with 1-3 halogenatoms; amino group optionally mono or di-substituted with the same or adifferent C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chain alkylgroup; thiol or thioether group having the same or different C₁-C₈straight-chain alkyl group or C₃-C₈ branched-chain alkyl group; sulfoneor sulfate group having the same or a different C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; nitro, cyano, halogen,hydroxy, carboxylic acid or sulfonic acid group; or alkoxy oralkoxycarbonyl group having the same or different a C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; Z is a bond, C₁-C₈straight-chain alkyl group, C₃-C₈ branched-chain alkyl group, 5-7membered saturated cyclic ring, 5-7 membered heterocyclic ring, 5-7membered aromatic ring or 5-7 membered heteroaromatic ring, each ofwhich is unsubstituted, mono-, di- or tri-substituted with: C₁-C₈straight-chain alkyl group, C₃-C₈ branched-chain alkyl group, C₂-C₈straight-chain alkenyl group, C₃-C₈ branched-chain alkenyl group, C₃-C₈straight chain alkynyl group, C₃-C₈ branched-chain alkynyl group, orphenyl group substituted at any ring position with one or more the sameor a different C₁-C₈ straight-chain alkyl group, C₃-C₈ branched-chainalkyl group, phenyl ring or heterocyclic ring, each of which isoptionally substituted with one or more the same or a different C₁-C₈straight-chain alkyl group, C₃-C₈ branched-chain alkyl group, C₁-C₈alkoxy group, C₁-C₈ alkoxycarbonyl group, carboxyl group, hydroxylgroup, nitro group, halogen atom or amino group, each of which isoptionally mono or di-substituted with the same or a different C₁-C₈straight-chain alkyl group or C₃-C₈ branched-chain alkyl group; methylgroup substituted with 1-3 halogen atoms; amino group optionally mono ordi-substituted with the same or a different C₁-C₈ straight-chain alkylgroup or C₃-C₈ branched-chain alkyl group; thiol or thioether grouphaving the same or different C₁-C₈ straight-chain alkyl group or C₃-C₈branched-chain alkyl group; sulfone or sulfate group having the same ora different C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chainalkyl group; nitro, cyano, halogen, hydroxy, carboxylic acid or sulfonicacid group; or alkoxy or alkoxycarbonyl group having the same ordifferent a C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chainalkyl group; Z is a bond, C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, 5-7 membered saturated cyclic ring, 5-7membered heterocyclic ring, 5-7 membered aromatic ring or 5-7 memberedheteroaromatic ring, each of which is unsubstituted, mono-, di- ortri-substituted with: C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₂-C₈ straight-chain alkenyl group, C₃-C₈branched-chain alkenyl group, C₂-C₈ straight chain alkynyl group, C₃-C₈branched-chain alkynyl group, or phenyl group substituted at any ringposition with one or more the same or a different C₁-C₈ straight-chainalkyl group, C₃-C₈ branched-chain alkyl group, phenyl ring orheterocyclic ring, each of which is optionally substituted with one ormore the same or a different C₁-C₈ straight-chain alkyl group, C₃-C₈branched-chain alkyl group, C₁-C₈ alkoxy group, C₁-C₈ alkoxycarbonylgroup, carboxyl group, hydroxyl group, nitro group, halogen atom oramino group, each of which is optionally mono or di-substituted with thesame or a different C₁-C₈ straight-chain alkyl group or C₃-C₈branched-chain alkyl group; methyl group substituted with 1-3 halogenatoms; amino group optionally mono or di-substituted with the same or adifferent C₁-C₈ straight-chain alkyl group or C₃-C₈ branched-chain alkylgroup; thiol or thioether group having the same or different C₁-C₈straight-chain alkyl group or C₃-C₈ branched-chain alkyl group; sulfoneor sulfate group having the same or a different C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; nitro, cyano, halogen,hydroxy, carboxylic acid or sulfonic acid group; or alkoxy oralkoxycarbonyl group having the same or different a C₁-C₈ straight-chainalkyl group or C₃-C₈ branched-chain alkyl group; wherein at least two ofW, Y and Z are not a bond, C₁-C₈ straight-chain alkyl group or C₃-C₈branched-chain alkyl group.
 8. The electroactive biocompatible polymeraccording to claim 7, wherein said arylsulfonium derivative istriphenylsulfonium salt; diphenyl[4-(phenylsulfanyl)phenyl]sulfoniumsalt; (4-fluorophenyl)(diphenyl)sulfonium salt;tris(4-tert-butylphenyl)sulfonium salt; tris(4-chlorophenyl)sulfoniumsalt; (4-chlorophenyl)diphenylsulfonium salt; tri-p-tolylsulfonium salt;tris(4-methoxyphenyl)sulfonium salt; (4-methoxyphenyl)diphenylsulfoniumsalt; ethyl(4-methoxyphenyl)(phenyl)sulfonium salt;(3-chloropropyl)diphenylsulfonium salt; or(5-chloropentyl)diphenylsulfonium salt.
 9. The electroactivebiocompatible polymer according to claim 1, wherein the electroactivebiocompatible polymer forms covalent crosslinking groups thereon oncethe electroactive biocompatible polymer is activated with a voltagepotential ranging from negative 10 Volts to positive 10 Volts.
 10. Theelectroactive biocompatible polymer according to claim 1, wherein theelectroactive biocompatible polymer forms covalent crosslinking groupsthereon once the electroactive biocompatible polymer is activated with avoltage potential applied constantly.
 11. The electroactivebiocompatible polymer according to claim 1, wherein the electroactivebiocompatible polymer forms covalent crosslinking groups thereon oncethe electroactive biocompatible polymer is activated with a voltagepotential applied variably.
 12. The electroactive biocompatible polymeraccording to claim 1, wherein the diazonium derivative, arylsulfoniumderivative, diaryliodonium derivative, and combinations thereof compriseCl⁻, Br⁻, I⁻, trifluoromethanesulfonate,dimethoxy-2-anthracenesulfonate, or methylbenzenesulfonate.